Project Summary/Abstract Candidate (Nazema Y. Siddiqui, MD, MHSc): My long-term goal is to improve the lives of women struggling with overactive bladder (OAB) and urgency urinary incontinence by conducting innovative translational research to improve therapeutic options. My first step towards that goal focuses on women with insulin resistance (IR) since this population is burdened by an especially high prevalence of OAB. I have developed a training program that builds on my clinical training in urologic conditions and prior advanced degree in clinical research. The K23 Award will provide me with essential mentored laboratory training, protected time, and dedicated coursework in genetics, epigenetics, bioinformatics, and molecular biology. Environment: I have an outstanding team of mentors that will support my training and transition to independence. These include Dr. Murphy, an expert in epigenomics and molecular biology; Dr. Amundsen, an expert in clinical OAB research; and Dr. Lucas, a biostatistician with expertise in complex pathway analyses. I will conduct my training at Duke University, a vibrant academic medical center with high quality clinical research infrastructure, molecular biology laboratories, and state-of-the-art Core Facilities that facilitate translational research. Research: My proposal will test the hypothesis that insulin resistance (IR) contributes to OAB through altered DNA methylation of urothelial genes involved in sensory nerve signaling. This hypothesis is based on: 1) the theory of bladder urothelial-afferent nerve signals giving rise to certain types of OAB; 2) data showing that urothelium acts as a sensor to traffic substances between the bladder lumen and suburothelial afferent nerve fibers; and 3) my preliminary data in voided cells of OAB-IR patients, where I discovered altered methylation in genes involved in signal transduction and vesicular trafficking to the cell membrane. In this proposal I will confirm the sites that are differentially methylated in voided cells from three well-characterized and matched cohorts of women +/- OAB and/or IR (Aim 1). Next, I will assess differential expression of genes involved in signal transduction, vesicular trafficking, and sensory nerve signaling (Aim 2). Finally, I will compare protein expression in bladder mucosal biopsies from a subset of patients in our four cohorts (Aim 3). Armed with these data and skills from this award, I will be uniquely suited to translate knowledge of these mechanistic pathways towards clinical implementation of new treatment strategies in women with OAB and insulin resistance.